Principles of Biochemistry, Volume 2 - A. Lehninger 1985

Bioenergetics and Metabolism
Fatty Acid Oxidation in Animal Tissues
The first stage of saturated fatty acid oxidation consists of four steps

Below, four enzymatic reactions that constitute the First stage of Fatty acid oxidation are examined.

a. The first dehydrogenation reaction

Поступившие в Cell/35.html">Митохондрии СоА- эфиры насыщенных жирных кислот подвергаются ферментативному дегидрированию по а- и ß-атомам углерода (т. е. по атомам углерода в положениях 2 и 3), в результате чего в углеродной цепи образуется двойная связь. Продуктом этой реакции, катализируемой ацил-СоА дегидрогеназой (обозначенной в приведенном ниже уравнении буквой Е), является транс-∆²-еноил-СоА. Простетической группой фермента служит FAD:

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Fig. 18-6. Fatty acid oxidation cycle. A. During the first turn of the cycle, one acetyl group (highlighted in red) is cleaved as acetyl-CoA from the carboxyl end of palmitic acid (C₁₆), which enters the cycle as palmitoyl-CoA. B. The next six turns of the cycle yield seven more molecules of acetyl-CoA (the seventh molecule is formed by the last two carbon atoms remaining from the 16-carbon chain of palmitic acid).

Fig. 18-7. Reducing equivalents removed from the fatty acid CoA derivative by acyl-CoA dehydrogenase (flavoprotein 3, or FP₃) are transferred via electron-transferring flavoprotein (ETF) to ubiquinone (Q), a component of the mitochondrial Respiratory Chain. For each pair of electrons transferred from ubiquinone to oxygen, two molecules of ATP are formed. Ubiquinone therefore collects electrons from NADH dehydrogenase (FP₁), succinate dehydrogenase (FP₂), and acyl-CoA dehydrogenase (FP₃).

The symbol Δ² conventionally designates THE POSITION OF the double bond (Fig. 18-6). It is important to note that the unsaturated compound formed in this reaction is a trans isomer; recall in this regard that the double bonds of Unsaturated Fatty acids found in natural compounds have the cis configuration (Section 12.1). We will return to discuss this apparent contradiction later. The hydrogen atoms removed from the fatty acid CoA esters are transferred to FAD, i.e., to the tightly bound prosthetic group of acyl-CoA dehydrogenase. The reduced form of acyl-CoA dehydrogenase then transfers a pair of electrons to a specific electron carrier called electron-transferring flavoprotein (ETF), which in turn transfers it to ubiquinone, a component of the mitochondrial respiratory chain (Fig. 18-7). As a result of the subsequent transfer of this electron pair along the respiratory chain to oxygen, two ATP molecules are generated via Oxidative Phosphorylation of ADP (Fig. 17-7).

b. Hydration reaction

The Second Stage of the fatty acid oxidation cycle involves the hydration of the double bond of trans-∆²-enoyl-CoA, yielding the L-stereoisomer of ß-hydroxy (or 3-hydroxy) acyl-CoA.

This reaction (Fig. 18-6) is catalyzed by enoyl-CoA hydratase (which has been obtained in crystalline form):

c. The second dehydrogenation reaction

In the Third Stage of the fatty acid oxidation cycle, L-3-hydroxyacyl-CoA is dehydrogenated to form 3-ketoacyl-CoA (Fig. 18-6). This reaction is catalyzed by 3-hydroxyacyl-CoA dehydrogenase, with NAD⁺ serving as the specific electron acceptor:

3-Hydroxyacyl-CoA dehydrogenase exhibits absolute Specificity for the L-стереоизомеров stereoisomers. The NADH formed in this reaction then transfers its reducing equivalents to NADH dehydrogenase of the respiratory chain (Fig. 18-7). For each pair of electrons passing down the Electron Transport Chain from NADH to oxygen, three molecules of ATP are generated, as is generally characteristic of all NAD-dependent substrate dehydrogenations occurring in Mitochondria (Sec. 17.13).

d. The thiolytic Cleavage reaction

The final (fourth) reaction of the fatty acid oxidation cycle is catalyzed by acetyl-CoA acetyltransferase (more commonly known as thiolase). At this stage, 3-ketoacyl-CoA reacts with free CoA—SH and undergoes cleavage to yield, first, a two-carbon fragment containing the two terminal carbon atoms of the original fatty acid in the form of acetyl-CoA, and second, the CoA ester of the fatty acid, now shortened by two carbon atoms (Fig. 18-6):

By analogy with Hydrolysis, this reaction is called thiolysis because ß-ketoacyl-CoA is cleaved as a result of its interaction with the thiol group of CoA (Fig. 18-6).